One strategy for treating human addiction is to target memory processes that underlie addictive behaviors. Repeated drug use establishes drug-related memories. When these drug-related memories are recalled, as occurs when the organism is re-exposed to drug-associated cues, context, or the drug itself, those memories are reconsolidated to maintain or strengthen them. The medial prefrontal cortex (mPFC) is a key contributor to relapse to cocaine-seeking behavior in humans and reinstatement behavior in rodents. Increased excitatory output from mPFC pyramidal neurons to the nucleus accumbens (NAc) is thought to underlie relapse. In rodents, this increased output is found after 5 cocaine injections and after 45 days of withdrawal from cocaine self-administration, implicating a key role for the mPFC in the maintenance of cocaine-associated memories. However, we do not know the mechanisms by which the mPFC contributes to the expression of these memories. Output from the mPFC is powerfully regulated by parvalbumin (PV)-fast-spiking GABAergic interneurons, the majority of which are surrounded by specialized extracellular matrix structures that form perineuronal nets (PNNs). PNNs envelope certain neurons during development and appear to stabilize synapses, reducing plasticity in neurons during adulthood. However, PNNs can be removed during adulthood to re-establish plasticity or to modify plasticity by other imposing stimuli. We have discovered that removal of PNNs within the rat prelimbic mPFC (PL mPFC) decreases the reconsolidation of cocaine-associated memories as tested with conditioned place preference (CPP; hereafter called cocaine CPP memory). Repeated cocaine exposure has the opposite effect: it increases PNN intensity, and this intensity is positively correlated with behavior, suggesting that PNN intensity in the PL mPFC may serve as a predictor of cocaine- induced behavior. A general layout of our experiments is as follows: Establish cocaine CPP memory? reactivate cocaine CPP memory PNNs? reconsolidate cocaine CPP memory? subsequent test for reinstatement of cocaine CPP memory to see if it is maintained or diminished. We propose that removal of PNNs from the PL mPFC prevents the maintenance of cocaine CPP memory via diminished memory reconsolidation. However, we do not know the mechanisms by which PNN removal decreases memory reconsolidation. We hypothesize that removal of PNNs within the PL mPFC modifies cocaine-induced plasticity during the reconsolidation of a cocaine CPP memory. We further hypothesize that reconsolidation is mediated by PNNs through altered activity of inhibitory interneurons and pyramidal neurons in the PL mPFC. We will train rats for cocaine-induced CPP in the presence and absence of PNNs and define the dynamic changes in PNN-surrounded neurons in the PL mPFC 1) just prior to and after memory reactivation; and 2) just prior to and after cocaine-induced reinstatement. We will use behavioral, electrophysiological, morphological, and confocal and electron microscopic approaches to test our hypotheses. PNNs are a highly novel target for dissecting events critical for cocaine-induced plasticity and the maintenance of cocaine-associated memories. Our findings will have potentially far-reaching consequences for understanding how already-formed cocaine memories can be disrupted by targeting PNN-surrounded neurons within the mPFC.